Optical techniques for tissue diagnosis without the removal of tissue are now being developed which offer significant advantages over standard techniques, such as tissue biopsy, both in terms of patient care and medical costs. For example, optical techniques are faster, sedatives are not needed, and complications associated with tissue removal such as infection are eliminated. The aim of this proposal is to develop and test polarized elastic scattering spectroscopy. Elastic scattering spectroscopy (ESS) measures the wavelength dependence of light that has entered the tissue, been scattered within the tissue and re-emitted. In polarized ESS the delivered light is polarized and the detected light is measured through polarizers. The detected light can provide information about both the morphological properties and the hemoglobin concentration. For example, a sensitivity to the rate at which cells are replicating has been demonstrated and measurements of model systems have shown that scatterer size and concentration can be determined. In order for this technique to reach its full potential an understanding of the fundamental interactions of light with tissue is needed. The first specific aim of this proposal is to determine how specific structural features of cells contribute to light scattering. The next aim will be to examine light scattering differences between tumorigenic and non-tumorigenic epithelial cells. Epithelial cells are particularly interesting, because most cancers originate from epithelial cells. Previous work demonstrated that the environment induced by cells in 3-D culture can cause a difference in light scattering from tumorigenic and non-tumorigenic cells. In parallel with the study of scattering properties improved measurement techniques will be developed and implemented for in vivo use. Finally, clinical trials will be performed to determine the utility of polarized elastic scattering spectroscopy to detect/diagnose squamous epithelium, reactive/repairing tissue, low grade dysplasia, high grade dysplasia and invasive carcinoma. Screening and diagnosis of cervical cancer is an ideal arena for the entry of optical techniques for cancer detection. The tissue is easily accessible and the low-accuracy Pap smear test has already demonstrated the utility of screening methods. ESS has the potentially to rapidly sample tissue and pinpoint locations of specific pathologies. Potentially ESS could replace Pap smears as a less frequent test or serve as an adjunct. If polarized ESS could be used to determine the significance of an ASCUS (atypical squamous cells of uncertain significance) Pap smear result, it could result in significant cost savings. ASCUS is the most common anomaly detected by Pan smears and annual follow up is estimated to cost 4.5 billion dollars per year.